Regulatory mechanism of doaminergic signal transduction in the striatum-bichemical studies.

在本研究中，我们试图从生物化学和药理学的角度阐明纹状体中多巴胺受体的功能机制，并探讨多巴胺能神经元活动的调控机制。结果表明：采用贝里奇（Berridge）方法对大鼠纹状体进行切片实验，观察混合多巴胺拮抗剂多巴胺或阿波啡刺激下的磷酸肌醇转换。结果，观察到PI， P2， P3释放增加，且这些增加呈剂量依赖性。使用SCH 23390或spiperone的抑制实验表明，这种PI转换的加速依赖于域胺D2受体。下一步，腹腔注射cck8类似物cerulein，观察CCK对大鼠地层多巴胺释放的影响。为此，进行了体内微透析实验，结果显示CCK对多巴胺释放的影响增加。此外，从直接早期基因的角度研究了神经肽与多巴胺的关系。注意到戊四唑诱导的c-fos的活化受到CCK和神经激肽的抑制，而这种抑制被多巴胺拮抗。此外，我们证实了这些神经肽抑制大鼠地层酪氨酸羟化酶基因的表达。需要强调的是，多巴胺和神经肽的信号转导之间存在着基因组和非基因组两个阶段的串扰。

In this studies, we tried to elucidate functional mechanism f doamine receptors in the striatum from biochemical and pharmacological viewpoints and discuss on mechanisms by which dopaminergic neuronal activtes are regulated. As results, following results were obtained.By means of slice experiments following Berridge's methds using rat striatum, phospatdyl inositol turnover stimulated by mixed dopamineagnist such as doamine or apomorphine was xamined. As results, increases of PI, P2, P3 reeases were bserved and these increases were dose-dependent.Inhibiton experiments by use of SCH 23390 or spiperone revealed that this acceeratin of PI turnver was dependent upon doamine D2 receptors.As next step, cerulein, a CCK 8 analog was ntraperitoneally injected to observe how CCK had effects on dopamine release from rat stratum. For this urpose, in vivo microdialsis experiments were done with the result of increasing effect of CCK on doamine release. In addition, relationship between neuropeptide and dopamine was studied from a viewpoint of immediate early genes. It was noticed that pentylentetrazole indused activation of c-fos was inhiited by bth CCK and neurokinin and such inhibition was antagonized by doamine. Furthermore, we confirmed that these neuropeptide inhibited gene expresion of tyrosine hydroxylase in rat stratum. Emphasis should be put on the fact that there were two hases of crosstalk, i.e. genomic and non-genomic, between sgnal transduction of dopamine and neuropeptides.